ABSTRACT Combination therapy including colistin and a carbapenem has been found to be associated with lower mortality in the treatment of bloodstream infections (BSI) due to KPC-producing Klebsiella pneumoniae when the isolates show a meropenem or imipenem MIC of <16 mg/liter. However, the optimal treatment of BSI caused by colistin- and high-level carbapenem-resistant KPC-producing K. pneumoniae is unknown. A prospective cohort study including episodes of bacteremia caused by colistin-resistant and high-level meropenem-resistant (MIC ≥ 64 mg/liter) KPC-producing K. pneumoniae diagnosed from July 2012 to February 2016 was performed. The impact of combination therapy on crude 30-day mortality was analyzed by Cox regression using a propensity score as a covariate to control for indication bias and in an inverse probability of treatment weighting (IPTW) cohort. The study sample comprised 104 patients, of which 32 (30.8%) received targeted monotherapy and 72 (69.2%) received targeted combination therapy; none of them received either colistin or a carbapenem. The 30-day crude mortality rate was 30.8% (43.8% in patients treated with monotherapy and 25% in patients receiving combination therapy). In the Cox regression analysis, 30-day mortality was independently associated with septic shock at BSI onset (hazard ratio [HR], 6.03; 95% confidence interval [CI], 1.65 to 21.9; P = 0.006) and admission to the critical care unit (HR, 2.87; 95% CI, 0.99 to 8.27; P = 0.05). Targeted combination therapy was associated with lower mortality only in patients with septic shock (HR, 0.14; 95% CI, 0.03 to 0.67; P = 0.01). These results were confirmed in the Cox regression analysis of the IPTW cohort. Combination therapy is associated with reduced mortality in patients with bacteremia due to colistin-resistant KPC-producing K. pneumoniae with high-level carbapenem resistance in patients with septic shock.